Molecular signatures of endocannabinoid induced pain relief in humans: lifestyle interventions, systemic and localised changes.

Endocannabinoids are molecules made by our bodies which are similar to some of the substances in marijuana. They regulate appetite, mood, sleep, muscle strength, inflammation and they also are involved in how strongly we feel and respond to pain. There have been efforts to generate new drugs that are similar to "endocannabinoids" to treat various diseases but because they are involved in so many functions these compounds end up having unforeseen side effects.

The microbes in our guts have been implicated in the levels of pain and inflammation that people experience. And physical exercises are well known to reduce the levels of pain experienced by people with chronic conditions such as arthritis.

We propose to understand (identify) the molecules that are involved in all of these related processes linked to pain by asking people to take fibre and or do exercise for six weeks, both of which increase endocannabinoid levels

We will measure levels of pain and pain sensitivity, peoples' mood, and take bloods to measure endocannabinoids, gut microbes, substances produced by microbes that alter inflammation, inflammatory substances, other pain related substances

The results of this study will help people with chronic pain in the following ways:
1. Understand the mechanisms by which lifestyle interventions like diet and exercise work and whether they can be added to each other to improve pain.
2. To measure how much of the effects of changes in endocannabinoids on pain reduction is linked to changes in mood or to changes in inflammation or to different levels of substances directly related to pain transmission and which genes in our bodies are involved
3. Understand if there are molecular factors that result in improved or reduced endocannabinoid changes and their effects on pain
4. Help develop new drugs to treat pain by understanding which mechanisms are modulated by the various receptors of drugs that target the endocannabinoid system

Modulation of endocannabinoids (ECB) in animal models has strong antinociceptive properties and use of cannabis appears effective in reducing neuropathic pain symptoms in humans. However, the pleiotropic effects of ECB receptors and the various feedback loops in the system make the prediction of undesirable central and peripheral effects of such compounds challenging, hindering the deployment of ECB targeting compounds to market. Endocannabinoid tone can also be modulated non-pharmacologically. Both physical exercise and alteration of the gut microbiome via dietary supplementation modify the endocannabinoid tone.
Strong clinical evidence that exercise interventions are effective in achieving clinically meaningful musculoskeletal pain relief. Observational and interventional evidence suggest that the gut microbiome is involved in pain intensity, progression and sensitivity for various types of pain.
We hypothesize (based on solid preliminary data) that the mechanisms by which these non-pharmacological interventions relieve pain are mostly mediated by modulation of the endocannabinoid system resulting in meaningful anti-inflammatory and antinociceptive effects
Using a factorial design of exercise and microbiome modulation of short chain fatty acids. We will perform extensive molecular phenotyping and characterisation of pain responses to these interventions and apply artificial intelligence/machine learning algorithms as we have done for other complex molecular traits. This will allow us to identify the key molecular mediators involved in effective responses to lifestyle interventions.
We will validate the pathways involved using independent cohorts such as TwinsUK, StepUp OA, IBEAT-OA with existing data on pain sensitivity and molecular markers.
Finally we will assess the direct relevance of ECs in the joint by assessing levels of ECs in synovial fluid from severe knee OA patients and their change with exercise/ gut microbiome modulating interventions